Treprostinil derivative compounds and methods of using same

ABSTRACT

Compounds represented by formulae I, II, III, and IV including pro-drugs for treprostinil and prostacyclin analogs. Uses include treatment of pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH). The structures of the compounds can be adapted to the particular application for a suitable treatment dosage. Transdermal applications can be used.

DESCRIPTION OF RELATED APPLICATIONS

This application claims priority to U.S. provisional application61/751,608 filed Jan. 11, 2013 which is incorporated herein by referencein its entirety for all purposes.

BACKGROUND

Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) isa disease which can result in death and is characterized by increasedpulmonary artery pressure and pulmonary vascular resistance. A needexists for better compounds and methods for treating PH and PAH. See,for example, US Patent Publication No. 2013/0274261. Many valuablepharmacologically active compounds, including some of interest withrespect to PH and PAH, cannot be effectively administered orally forvarious reasons and are generally administered via intravenous orintramuscular routes. These routes of administration generally requireintervention by a physician or other health care professional, and canentail considerable discomfort as well as potential local trauma to thepatient. One example of such a compound is treprostinil and derivativesthereof, which has been used in the treatment of PH and PAH. See, forexample, WO 2005/007081. The core chemical formula is (herein alsolabeled, Compound A):

including pharmaceutically acceptable salts such as the sodium salt.

Accordingly, there is a clinical need in providing treprostinil byimproved formulations and methods, e.g., either orally or transdermally.More particularly, there is a need for a safe and effective method forincreasing the systemic availability of treprostinil via administrationof treprostinil or treprostinil analogs.

The application of transdermal drug delivery technology to theadministration of a wide variety of drugs has been proposed and varioussystems for accomplishing this are disclosed in numerous technicaljournals and patents. U.S. Pat. Nos. 3,598,122, 4,144,317, 4,201,211,4,262,003, and 4,379,454, all of which are incorporated herein byreference, are representative of various transdermal drug deliverysystems of the prior art, which systems have the ability of deliveringcontrolled amounts of drugs to patients for extended periods of timeranging in duration from several hours to several days. None of theabove patents nor any other prior art of which the inventors are awaredescribes a transdermal delivery system which is intended to delivertreprostinil or its derivatives nor are they aware of data on skinpermeability or therapeutic transdermal delivery rates adequate todesign such a system.

SUMMARY

Embodiments described herein including compounds, compositions, anddevices, as well as methods of making and methods of using the same.

One embodiment provides a compound represented by Formula (I)

wherein, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁,R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are independently H or deuterium;

Z is —OH, —OR₁₁, —N(R₁₁)R₁₂, —SR₁₁, or P₁;

R₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, alkylcycloalkyl, substitutedalkylcycloalkyl, alkylcycloheteroalkyl, substitutedalkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substitutedalkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, orsubstituted alkylheteroaryl;R₁₂ is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,alkylcycloheteroalkyl, aryl, or heteroaryl;P₁ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;R₁₄ and R₁₅ are independently in each occurrence selected from the groupconsisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl,heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, substituted aryl, substituted heteroaryl, substitutedarylalkyl, and substituted heteroarylalkyl;R₁₄ and R₁₅ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring optionally incorporating one ortwo ring heteroatoms chosen from N, O, or S, which is unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halo, methyl, and methoxy;R₁₈ and R₁₉ are independently in each occurrence selected from the groupconsisting of hydrogen and alkyl, wherein the alkyl is unsubstituted orsubstituted with 1 substituent selected from the list consisting ofhalo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl),—CONH₂, aryl, and heteroaryl, wherein the aryl or heteroaryl areunsubstituted or substituted from the list consisting of alkyl, halo,haloalkyl, hydroxy, and alkoxy, haloalkoxy;R₁₄ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₄ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₅ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₅ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;and, R₁ and R₂ are independently H or P₂, wherein at least one of R₁ andR₂ is P₂, whereinP₂ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;R₁₄ and R₁₅ are as defined above;R₁₄ and R₁₅ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring optionally incorporating one ortwo ring heteroatoms chosen from N, O, or S, which is unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected from thelist consisting of halo, methyl and methoxy;R₁₆ and R₁₇ are independently in each occurrence H or alkyl;R₁₆ and R₁₇ taken together with the atoms to which they attachoptionally form a 3- to 6-membered ring;R₁₈ and R₁₉ are as defined above;R₁₄ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₄ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;wherein Formula I includes enantiomers, pharmaceutically acceptablesalts, and polymorphs of the compounds of Formula I.

In another embodiment, the parameters of Formula I are defined asfollows:

R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃,R₃₄, R₃₅, and R₃₆ are independently H or deuterium;

Z is −OR₁₁, —N(R₁₁)R₁₂, —SR₁₁, or P₁;

R₁₁ is branched alkyl, haloalkyl, halocycloalkyl, heteroalkyl,substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,bicycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl,alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, alkylaryl,substituted alkylaryl, heteroaryl, substituted heteroaryl,alkylheteroaryl, substituted alkylheteroaryl;R₁₂ is H, branched alkyl, haloalkyl, heteroalkyl, cycloheteroalkyl,alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;P₁ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;R₁₄ and R₁₅ are independently in each occurrence selected from the groupconsisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl,heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, substituted aryl, substituted heteroaryl, substitutedarylalkyl, and substituted heteroarylalkyl;R₁₄ and R₁₅ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring optionally incorporating one ortwo ring heteroatoms chosen from N, O, or S, which is unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halo, methyl, and methoxy;R₁₈ and R₁₉ are independently in each occurrence selected from the groupconsisting of hydrogen and alkyl, wherein the alkyl is unsubstituted orsubstituted with 1 substituent selected from the list consisting ofhalo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl),—CONH₂, aryl, and heteroaryl, wherein the aryl or heteroaryl areunsubstituted or substituted from the list consisting of alkyl, halo,haloalkyl, hydroxy, and alkoxy, haloalkoxy;R₁₄ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₄ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₅ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₅ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;and, R₁ and R₂ are independently H or P₂, whereinP₂ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;R₁₄ and R₁₅ are as defined above;R₁₄ and R₁₅ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring optionally incorporating one ortwo ring heteroatoms chosen from N, O, or S, which is unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected from thelist consisting of halo, methyl and methoxy;R₁₆ and R₁₇ are independently in each occurrence H or alkyl;R₁₆ and R₁₇ taken together with the atoms to which they attachoptionally form a 3- to 6-membered ring;R₁₈ and R₁₉ are as defined above;R₁₄ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₄ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;wherein Formula I includes enantiomers, pharmaceutically acceptablesalts, and polymorphs of the compounds of Formula I.

In another embodiment, provided is a compound represented by Formula II:

wherein,R₂ is selected from the group consisting of H and P₂;R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃,R₃₄, R₃₅, and R₃₆ are independently selected from the group consistingof H and deuterium;L₁ is a selected from the group consisting of —O-alkylene-C(O)—,—O-alkylene-OC(O)—, or a bond; whereinP₂ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;R₁₄ and R₁₅ are as defined above;R₁₄ and R₁₅ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring optionally incorporating one ortwo ring heteroatoms chosen from N, O, or S, which is unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected from thelist consisting of halo, methyl and methoxy;R₁₆ and R₁₇ are independently in each occurrence H or alkyl;R₁₆ and R₁₇ taken together with the atoms to which they attachoptionally form a 3- to 6-membered ring;R₁₈ and R₁₉ are as defined above;R₁₄ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₄ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;wherein Formula II includes enantiomers, pharmaceutically acceptablesalts, and polymorphs of the compounds of Formula II.

In another embodiment, a compound is represented by Formula III:

L₂ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;

X is NR₁₄, or O;

R₁₄ is selected from the group consisting of H, alkyl, cycloalkyl,alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substitutedheteroaryl, substituted arylalkyl, substituted heteroarylalkyl;R₁₆ and R₁₇ are independently in each occurrence H or alkyl;R₁₆ and R₁₇ taken together with the atoms to which they attachoptionally form a 3- to 6-membered ring; andR₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃,R₃₄, R₃₅, and R₃₆ are independently selected from the group consistingof H and deuterium;wherein Z is —OH, —OR₁₁, —N(R₁₁)R₁₂, —SR₁₁, or P₁;R₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, alkylcycloalkyl, substitutedalkylcycloalkyl, alkylcycloheteroalkyl, substitutedalkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substitutedalkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, orsubstituted alkylheteroaryl;R₁₂ is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,alkylcycloheteroalkyl, aryl, or heteroaryl;P₁ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;R₁₄ and R₁₅ are independently in each occurrence selected from the groupconsisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl,heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, substituted aryl, substituted heteroaryl, substitutedarylalkyl, and substituted heteroarylalkyl;R₁₄ and R₁₅ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring optionally incorporating one ortwo ring heteroatoms chosen from N, O, or S, which is unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halo, methyl, and methoxy;R₁₈ and R₁₉ are independently in each occurrence selected from the groupconsisting of hydrogen and alkyl, wherein the alkyl is unsubstituted orsubstituted with 1 substituent selected from the list consisting ofhalo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl),—CONH₂, aryl, and heteroaryl, wherein the aryl or heteroaryl areunsubstituted or substituted from the list consisting of alkyl, halo,haloalkyl, hydroxy, and alkoxy, haloalkoxy;R₁₄ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₄ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₅ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₅ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;wherein Formula III includes enantiomers, pharmaceutically acceptablesalts, and polymorphs of the compounds of Formula III.

Another embodiment provides a compound represented by Formula IV:

R₁ is selected from the group consisting of H and P₂;R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃,R₃₄, R₃₅, and R₃₆ are independently selected from the group consistingof H and deuterium;L₁ is a selected from the group consisting of —O-alkylene-C(O)—,—O-alkylene-OC(O)—, or a bond; whereinP₂ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;R₁₄ and R₁₅ are independently in each occurrence selected from the groupconsisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl,heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, substituted aryl, substituted heteroaryl, substitutedarylalkyl, and substituted heteroarylalkyl;R₁₄ and R₁₅ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring optionally incorporating one ortwo ring heteroatoms chosen from N, O, or S, which is unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halo, methyl, and methoxy;R₁₆ and R₁₇ are independently in each occurrence H or alkyl;R₁₆ and R₁₇ taken together with the atoms to which they attachoptionally form a 3- to 6-membered ring;R₁₈ and R₁₉ are independently in each occurrence selected from the groupconsisting of hydrogen and alkyl, wherein the alkyl is unsubstituted orsubstituted with 1 substituent selected from the list consisting ofhalo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl),—CONH₂, aryl, and heteroaryl, wherein the aryl or heteroaryl areunsubstituted or substituted from the list consisting of alkyl, halo,haloalkyl, hydroxy, and alkoxy, haloalkoxy;R₁₄ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₄ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;wherein Formula IV includes enantiomers, pharmaceutically acceptablesalts, and polymorphs of the compounds of Formula IV.

Compositions are also provided including a composition comprising atleast one compound according to Formula I, II, III, and IV and at leastone other component. In one embodiment, the composition is formulatedfor transdermal delivery. In another embodiment, the composition isformulated for transdermal delivery with a patch. In one embodiment, thecomposition can further comprise at least one solvent. In oneembodiment, the amount of the compound according to Formula I, II, III,or IV is adapted to provide a useful delivery profile for treatment of ahuman. In one embodiment, the treatment is carried out on a subject,such as a mammal, but the subject is not a human.

At least one advantage for at least one embodiment includes ability totailor the chemical structure of a pharmaceutically useful motif for aparticular uses including treatment and prophylactic use against, forexample, PH and PAH. For example, the drug delivery profile can beadapted for a particular application.

At least one additional advantage for at least one embodiment includesability to use the compounds to provide better bioavailability includinguse in transdermal drug delivery applications.

DETAILED DESCRIPTION Introduction

Priority U.S. provisional application 61/751,608 filed Jan. 11, 2013 isincorporated herein by reference in its entirety for all purposesincluding the chemical formulae and claims, including Formula I, FormulaII, and Formula III, as well as Schemes 1-4, examples, and the tables ofstructures on pages 14-16.

Various prostacyclin analogs, including treprostinil, and methods fortheir use are known. For example, they can be used in promotingvasodilation, inhibiting platelet aggregation and thrombus formation,stimulating thrombolysis, inhibiting cell proliferation (includingvascular remodeling), providing cytoprotection, and preventingatherogenesis and inducing angiogenesis. Through theseprostacyclin-mimetic mechanisms, these compounds may be used in thetreatment of/for: pulmonary hypertension, ischemic diseases (e.g.,peripheral vascular disease, Raynaud's phenomenon, Scleroderma,myocardial ischemia, ischemic stroke, renal insufficiency), heartfailure (including congestive heart failure), conditions requiringanticoagulation (e.g., post MI, post cardiac surgery), thromboticmicroangiopathy, extracorporeal circulation, central retinal veinocclusion, atherosclerosis, inflammatory diseases (e.g., COPD,psoriasis), hypertension (e.g., preeclampsia), reproduction andparturition, cancer or other conditions of unregulated cell growth,cell/tissue preservation, and other emerging therapeutic areas whereprostacyclin treatment appears to have a beneficial role. Thesecompounds may also demonstrate additive or synergistic benefit incombination with other cardiovascular agents (e.g., calcium channelblockers, phosphodiesterase inhibitors, endothelial antagonists, andantiplatelet agents).

Treprostinil is a chemically stable analog of prostacyclin. Althoughtreprostinil sodium (Remodulin®) is approved by the Food and DrugAdministration (FDA) for subcutaneous administration, treprostinil asthe free acid has an absolute oral bioavailability of less than 10% anda very short systemic half life due to significant metabolism.

DEFINITIONS

Herein, listings of chemical groups represented by multiple chemicalformulae are provided (e.g., P₁, P₂, L₁, and L₂). As used herein, thesegroup listings also describe any combination of subgroups of thechemical formulae in the group listing as well as any single formula inthe group listing.

The Wall “alkyl,” as used herein, refers to a monovalent saturatedhydrocarbon group. C₁-C₈ alkyl is an alkyl having from 1 to 8 carbonatoms and includes, for example, C₁-C₃ alkyl, C₁-C₅ alkyl, and C₁-C₇alkyl. An alkyl may be linear or branched. Examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl.

The term “haloalkyl,” as used herein, refers monovalent saturatedhydrocarbon group attached to a one or more halogen selected from Cl andF, Specific examples include 2-fluoroethyl, 2,2-difluoroethyl,2-fluoropropyl, and 2,2-difluoropropyl.

The term “heteroalkyl,” as used herein, refers to a monovalent saturatedhydrocarbon group attached to one or more hetero atoms selected from O,N, and S. C₁-C₈ heteroalkyl is an alkyl having from 1 to 8 carbon atomsfollowed by a heteroatom selected from O, N, S and includes, forexample, C₁-C₃—OH, C₁-C₅—SH, and C₁-C₇—NH₂. It also includesC1-C2-O—C3-C4-OH, and C1-C2-NH—C3-C4-OH

The term “cycloalkyl,” as used herein, refers to a monocyclic, bicyclic,or tricyclic monovalent saturated hydrocarbon ring system. The term“C₃-C₁₄ cycloalkyl” refers to a cycloalkyl wherein the number of ringcarbon atoms is from 3 to 14. Examples of C₃-C₁₄ cycloalkyl includeC₃-C₁₀ cycloalkyl and C₃-C₆ cycloalkyl. Bicyclic and tricyclic ringsystems include fused, bridged and spirocyclic ring systems. Moreparticular examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cis- andtrans-decalynil, norbornyl, adamantyl, and spiro[4,5]decanyl.

The term “cycloheteroalkyl,” as used herein, refers to a monocyclic,bicyclic, or tricyclic monovalent saturated ring system wherein from 1to 4 ring atoms are heteroatoms independently selected from the groupconsisting of O, N and S. The term “3 to 14-membered cycloheteroalkyl”refers to a cycloheteroalkyl wherein the number of ring atoms is from 3to 14. Examples of 3 to 14-membered cycloheteroalkyl include 3 to10-membered cycloheteroalkyl and 3 to 6-membered cycloheteroalkyl.Bicyclic and tricyclic ring systems include fused, bridged andspirocyclic ring systems. More particular examples of cycloheteroalkylgroups include azepanyl, azetidinyl, aziridinyl, imidazolidinyl,morpholinyl, oxazolidinyl, oxazolidinyl, piperazinyl, piperidinyl,pyrazolidinyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,thiomorpholinyl, and α-methyl-1,3-dioxol-2-onyl.

The term “alkylcycloalkyl,” as used herein, refers to a monocyclic,bicyclic, or tricyclic monovalent saturated hydrocarbon ring system. Theterm “C₃-C₁₄cycloalkyl” refers to a cycloalkyl wherein the number ofring carbon atoms is from 3 to 14. Examples of C₃-C₁₄ cycloalkyl includeC₃-C₁₀ cycloalkyl and C₃-C₆cycloalkyl. Bicyclic and tricyclic ringsystems include fused, bridged, and spirocyclic ring systems linked toan alkyl group which refers to a monovalent saturated hydrocarbon group.C₁-C₈ alkyl is an alkyl having from 1 to 8 carbon atoms and includes,for example, C₁-C₃ alkyl, C₁-C₅ alkyl, and C₁-C₇ alkyl, Particularexamples include cyclopropyl methyl, cyclopropyl ethyl, and cyclohexylethyl.

The term “alkylheterocycloalkyl,” as used herein, refers to an alkylthat refers to a monovalent saturated hydrocarbon group. C₁-C₈ alkyl isan alkyl having from 1 to 8 carbon atoms and includes, for example,C₁-C₃ alkyl, C₁-C₅ alkyl, and C₁-C₇ alkyl attached to cycloalkyl whichrefers to a monocyclic, bicyclic, or tricyclic monovalent saturated ringsystem wherein from 1 to 4 ring atoms are heteroatoms independentlyselected from the group consisting of O, N, and S. The term “3 to14-membered heterocycloalkyl” refers to a heterocycloalkyl wherein thenumber of ring atoms is from 3 to 14. Examples of 3 to 14-memberedheterocycloalkyl include 3 to 10-membered heterocycloalkyl and 3 to6-membered heterocycloalkyl. Bicyclic and tricyclic ring systems includefused, bridged and spirocyclic ring systems. Specific examples includeN-ethylmorpholine, N-ethylpiperidine, 4-ethylpiperidine,1-methyl-4-ethylpiperidine, and N-ethylpiperazine.

The term “aryl,” as used herein, refers to a monovalent aromaticcarbocyclic ring system, which may be a monocyclic, fused bicyclic, orfused tricyclic ring system. The term “C₆-C₁₄ aryl” refers to an arylhaving from 6 to 14 ring carbon atoms. An example of C₆-C₁₄ aryl isC₆-C₁₀ aryl. More particular examples of aryl groups include phenyl,naphthyl, anthracyl, and phenanthryl.

The term “heteroaryl,” as used herein, refers to unsaturated aromaticheterocyclyl radicals. Examples of heteroaryl radicals includeunsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl,tetrazolyl, etc; unsaturated condensed heterocyclyl group containing 1to 5 nitrogen atoms, for example, indolyl, isoindolyl, benzimidazolyl,quinolyl, benzotrazolyl, tetrazolopyridazinyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, oxadiazolyl, etc.;unsaturated condensed heterocyclyl group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms; unsaturated 3- to 6-membered heteromonocyclicgroup containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, forexample, thiazolyl, thiadiazolyl, etc.; and unsaturated condensedheterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogenatoms.

The term “alkylaryl,” as used herein, refers to aryl-substituted alkylradicals such as benzyl, diphenyl methyl, and phenylethyl.

The term “alkylheteroaryl,” as used herein, refers toheteroaryl-substituted alkyl radicals such as imidazoylmethyl,thiazoylmethyl, and pyridylethyl.

As used herein, the terms described herein such as alkyl, haloalkyl,heteroalkyl, cycloalkyl, cycloheteroalkyl, alkylcycloalkyl,alkylheterocycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroary,are understood to cover in some optional embodiments wherein they formrings. For example, as described further herein, in some cases,optionally, groups such as R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, and R₁₉ can formrings with other groups R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, and R₁₉.

The Wall substituted refers to the replacement, of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent including, but not limited to: halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,alkylsulfonyl, alkylsulfonylalkyl, alkoxy, alkoxy, aryloxy,aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aryloxycarbonyl, alkylhalo, amino, trifluoromethyl, cyano, nitro,alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, hydroxyl,alkyloxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,acyl, carbonyl, carboxylic acid sulfonic acid, phosphoric acid, aryl,heteroaryl, heterocyclic, and aliphatic. It is understood that thesubstituent may be further substituted within the normal limits of theskilled artisan. A moiety or group may be optionally substituted whichmeans the group may or may not have one or more substituents.

The term “compound” as used herein, is also intended to include salts,solvates, and hydrates thereof. The specific recitation of “salt,”“solvate,” or “hydrate,” in certain aspects of the invention describedin this application shall not be interpreted as an intended omission ofthese forms in other aspects of the invention where the term “compound”is used without recitation of these other forms.

A salt of a compound of this invention is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. According to another preferred embodiment, the compound is apharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any non-toxic salt that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound or a prodrug of a compound of this invention. A“pharmaceutically acceptable counterion” is an ionic portion of a saltthat is not toxic when released from the salt upon administration to arecipient.

Acids commonly employed to form pharmaceutically acceptable saltsinclude inorganic acids such as hydrogen bisulfide, hydrochloric,hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well asorganic acids such as para-toluenesulfonic, salicylic, tartaric,bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic,formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic,lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric,benzoic and acetic acid, and related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, sulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate,.beta.-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate,propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,mandelate and the like salts. Preferred pharmaceutically acceptable acidaddition salts include those formed with mineral acids such ashydrochloric acid and hydrobromic acid, and especially those formed withorganic acids such as maleic acid.

As used herein, the term “hydrate” means a compound which furtherincludes a stoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces.

As used herein, the term “solvate” means a compound which furtherincludes a stoichiometric or non-stoichiometric amount of solvent suchas water, acetone, ethanol, methanol, dichloromethane, 2-propanol, orthe like, bound by non-covalent intermolecular forces.

Isotopes and Isotopic Abundance

It will be recognized that some variation of natural isotopic abundanceoccurs in a synthesized compound depending upon the origin of chemicalmaterials used in the synthesis. Thus, a preparation of treprostinilwill inherently contain small amounts of deuterated isotopologues. Theconcentration of naturally abundant stable hydrogen and carbon isotopes,notwithstanding this variation, is small and immaterial with respect tothe degree of stable isotopic substitution of compounds of thisinvention. See, for instance, Wada E et al, Seikagaku 1994, 66:15; GanesL Z et al, Comp Biochem Physiol Mol Integr Physiol 1998, 119:725. In acompound of this invention, when a particular position is designated ashaving deuterium, it is understood that the abundance of deuterium atthat position is substantially greater than the natural abundance ofdeuterium, which is 0.015%. A position designated as having deuteriumtypically has a minimum isotopic enrichment factor of at least 3000 (45%deuterium incorporation) at each atom designated as deuterium in saidcompound.

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope.

In some embodiments, a compound of this invention has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

In the compounds of this invention any atom not specifically designatedas a particular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition.

In other embodiment, a compound of the invention contains less than 10%,preferably less than 6%, and more preferably less than 3% of all otherisotopologues combined, including a form that lacks any deuterium. Incertain aspects, the compound contains less than “X”% of all otherisotopologues combined, including a form that lacks any deuterium; whereX is any number between 0 and 10 (e.g., 1, 0.5, 0.001), inclusive.Compositions of matter that contain greater than 10% of all otherisotopologues combined are referred to herein as “mixtures” and mustmeet the parameters set forth below. These limits of isotopiccomposition and all references to isotopic composition herein, refersolely to the relative amounts of deuterium/hydrogen present in theactive, free base form of the compound of Formula I or II, and do notinclude the isotopic composition of hydrolyzable portions of prodrugs,or of counterions.

The term “isotopologue” refers to species that differ from a specificcompound of this invention only in the isotopic composition of theirmolecules or ions.

Core Structure Formula I

In one embodiment, the present invention provides a compound representedby Formula I:

At least two sub-embodiments are provided to define further Formula I.

In a first sub-embodiment of Formula I, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅,R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ areindependently H or deuterium;

Z is —OH, —OR₁₁, —N(R₁₁)R₁₂, —SR₁₁, or P₁;

R₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, alkylcycloalkyl, substitutedalkylcycloalkyl, alkylcycloheteroalkyl, substitutedalkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substitutedalkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, orsubstituted alkylheteroaryl;R₁₂ is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,alkylcycloheteroalkyl, aryl, or heteroaryl;P₁ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;R₁₄ and R₁₅ are independently in each occurrence selected from the groupconsisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl,heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, substituted aryl, substituted heteroaryl, substitutedarylalkyl, and substituted heteroarylalkyl;R₁₄ and R₁₅ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring optionally incorporating one ortwo ring heteroatoms chosen from N, O, or S, which is unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halo, methyl, and methoxy;R₁₈ and R₁₉ are independently in each occurrence selected from the groupconsisting of hydrogen and alkyl, wherein the alkyl is unsubstituted orsubstituted with 1 substituent selected from the list consisting ofhalo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl),—CONH₂, aryl, and heteroaryl, wherein the aryl or heteroaryl areunsubstituted or substituted from the list consisting of alkyl, halo,haloalkyl, hydroxy, and alkoxy, haloalkoxy;R₁₄ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₄ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₅ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₅ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;and, R₁ and R₂ are independently H or P₂, wherein at least one of R₁ andR₂ is P₂, whereinP₂ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;R₁₄ and R₁₅ are as defined above;R₁₄ and R₁₅ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring optionally incorporating one ortwo ring heteroatoms chosen from N, O, or S, which is unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected from thelist consisting of halo, methyl and methoxy;R₁₆ and R₁₇ are independently in each occurrence H or alkyl;R₁₆ and R₁₇ taken together with the atoms to which they attachoptionally form a 3- to 6-membered ring;R₁₈ and R₁₉ are as defined above;R₁₄ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₄ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;wherein Formula I includes enantiomers, pharmaceutically acceptablesalts, and polymorphs of the compounds of Formula I. In this Formula I,the Z, R₁, and R₂ groups are not linked to each other, in contrast toFormulae II, III, and IV described herein.

In one embodiment, R₁ is P₂ and R₂ is H. In another embodiment, R₁ is Hand R₂ is P₂. In another embodiment, R₁ is P₂ and R₂ is P₂.

The group P₂ can be more particularly described. In one embodiment, P₂is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In one embodiment, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉,R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are H.

In one embodiment, Z is −OR₁₁, —N(R₁₁)R₁₂, or P₁. In another embodiment,Z is P₁. In another embodiment, Z is —OH, —OR₁₁, —N(R₁₁)R₁₂, or P₁. Inanother embodiment, Z is —OH.

In one embodiment, Z is not —OH and R₁₁ is not unsubstituted orsubstituted benzyl.

In a second sub-embodiment of Formula I,

R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃,R₃₄, R₃₅, and R₃₆ are independently H or deuterium;

Z is −OR₁₁, —N(R₁₁)R₁₂, —SR₁₁, or P₁;

R₁₁ is branched alkyl, haloalkyl, halocycloalkyl, heteroalkyl,substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,bicycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl,alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, alkylaryl,substituted alkylaryl, heteroaryl, substituted heteroaryl,alkylheteroaryl, substituted alkylheteroaryl;R₁₂ is H, branched alkyl, haloalkyl, heteroalkyl, cycloheteroalkyl,alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;P₁ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;R₁₄ and R₁₅ are independently in each occurrence selected from the groupconsisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl,heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, substituted aryl, substituted heteroaryl, substitutedarylalkyl, and substituted heteroarylalkyl;R₁₄ and R₁₅ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring optionally incorporating one ortwo ring heteroatoms chosen from N, O, or S, which is unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halo, methyl, and methoxy;R₁₈ and R₁₉ are independently in each occurrence selected from the groupconsisting of hydrogen and alkyl, wherein the alkyl is unsubstituted orsubstituted with 1 substituent selected from the list consisting ofhalo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl),—CONH₂, aryl, and heteroaryl, wherein the aryl or heteroaryl areunsubstituted or substituted from the list consisting of alkyl, halo,haloalkyl, hydroxy, and alkoxy, haloalkoxy;R₁₄ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₄ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₅ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₅ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;and, R₁ and R₂ are independently H or P₂, whereinP₂ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;R₁₄ and R₁₅ are as defined above;R₁₄ and R₁₅ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring optionally incorporating one ortwo ring heteroatoms chosen from N, O, or S, which is unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected from thelist consisting of halo, methyl and methoxy;R₁₆ and R₁₇ are independently in each occurrence H or alkyl;R₁₆ and R₁₇ taken together with the atoms to which they attachoptionally form a 3- to 6-membered ring;R₁₈ and R₁₉ are as defined above;R₁₄ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₄ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;wherein Formula I includes enantiomers, pharmaceutically acceptablesalts, and polymorphs of the compounds of Formula I.

In one embodiment, Z is —OR₁₁. In one embodiment, Z is —N(R₁₁)R₁₂. Inone embodiment, Z is —SR₁₁. In one embodiment, Z is P₁. In oneembodiment, Z is OR₁₁ and R₁₁ is bicycloalkyl, alkylcycloalkyl, oralkylcycloheteroalkyl. In one embodiment, Z is P₁.

In one embodiment, R₁₁ is haloalkyl, or more particularly, fluoroalkyl.

In one embodiment, R₁ is hydrogen or R₂ is hydrogen. In one embodiment,R₁ is hydrogen and R₂ is P₂. In one embodiment, R₁ is P₂ and R₂ ishydrogen. In one embodiment, R₁ and R₂ are hydrogen. In one embodiment,R₁ and R₂ are P₂.

In one embodiment, at least one of R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆,R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are deuterium.

In one embodiment, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉,R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are hydrogen.

Formula IA

One particular sub-embodiment also for formula I is a compoundrepresented by Formula (IA):

wherein,

Z is —OH, —OR₁₁, or P₁;

R₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, alkylcycloalkyl, substitutedalkylcycloalkyl, alkylcycloheteroalkyl, substitutedalkylcycloheteroalkyl,P₁ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;R₁₄ is selected from the group consisting of H, alkyl, cycloalkyl,alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, substituted aryl, substituted heteroaryl, substitutedarylalkyl, and substituted heteroarylalkyl;and, R₁ and R₂ are independently H or P₂, wherein at least one of R₁ andR₂ is P₂, whereinP₂ is selected from the group consisting of:

wherein,R₁₄ and R₁₅ are independently in each occurrence selected from the groupconsisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substitutedheteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;R₁₄ and R₁₅ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;wherein Formula IA includes enantiomers, pharmaceutically acceptablesalts, and polymorphs of the compounds of Formula IA.

Specific Compounds for Formula I

The following are specific compounds for formula I (noting Compound Awhich as discussed hereinabove is the control, not a pro-drug):

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid cyclopropylmethyl ester

N-Cyclopropylmethyl-2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetamide

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 2-morpholin-4-yl-ethyl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 3-fluoro-propyl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid tetrahydro-furan-3-yl ester

2-{2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetoxy}-propionicacid methyl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid

N-(2-Hydroxy-ethyl)-2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetamide

N-(2-Amino-ethyl)-2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetamide

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 2-hydroxy-ethyl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 2-methoxy-ethyl ester

2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(3-hydroxy-propyl)-acetamide

{2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetylamino}-aceticacid methyl ester

({2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetyl}-methyl-amino)-aceticacid methyl ester

2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(2,2,2-trifluoro-ethyl)-acetamide

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 2,2-dimethyl-propyl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2-dimethyl-propyl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2,2-trimethyl-propyl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid bicyclo[2.2.1]hept-2-yl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid isopropyl ester

2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(2,2,3,3,3-pentafluoro-propyl)-acetamide

Pentanoic acid1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ylester

3-Methyl-butyric acid1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ylester

Cyclopropanecarboxylic acid1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ylester

[2-Ethoxycarbonyloxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester

[2-Acetoxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester

Succinic acid ethyl ester1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ylester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid tert-butyl ester

3-{2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetyl}-oxazolidin-2-one

2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(1H-tetrazol-5-yl)-acetamide

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 2,2,2-trifluoro-1,1-dimethyl-ethyl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2,2-trimethyl-propyl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2,2-trimethyl-propyl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid bicyclo[2.2.1]hept-2-yl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid bicyclo[2.2.1]hept-2-yl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid bicyclo[2.2.1]hept-2-yl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid bicyclo[2.2.1]hept-2-yl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 2-isopropyl-5-methyl-cyclohexyl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl ester

[2-(2-Ethoxy-ethoxycarbonyloxy)-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester

[2-(2-Dimethylamino-ethoxycarbonyloxy)-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester

[1-(3-Hydroxy-octyl)-2-(2,2,2-trifluoro-ethoxycarbonyloxy)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester

3-Morpholin-4-yl-propionic acid1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ylester

[1-(3-Hydroxy-octyl)-2-(2-pyrrolidin-1-yl-acetoxy)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester

Cyclopentanecarboxylic acid1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexylester

1-Methyl-piperidine-2-carboxylic acid1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexylester

4-Methyl-morpholine-2-carboxylic acid1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexylester

Cyclopropanecarboxylic acid1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexylester

2-Methyl-butyric acid1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexylester

[1-(3-Cyclopentyloxycarbonyloxy-octyl)-2-hydroxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester

{1-[3-(1-Aza-bicyclo[2.2.2]oct-3-yloxycarbonyloxy)-octyl]-2-hydroxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}-aceticacid methyl ester

[2-Acetoxy-1-(3-acetoxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1-aza-bicyclo[2.2.2]oct-3-yl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1-aza-bicyclo[2.2.2]oct-3-yl ester

Propionic acid1-{2-[5-methoxycarbonylmethoxy-2-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyloxy)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl]-ethyl}-hexylester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2-dimethyl-propyl ester

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2-dimethyl-propyl ester Core Structure Formulae II and IIA

In another embodiment, the present invention provides a compoundrepresented by Formula II:

wherein,R₂ is selected from the group consisting of H and P₂;R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃,R₃₄, R₃₅, and R₃₆ are independently selected from the group consistingof H, deuterium;L₁ is a selected from the group consisting of —O-alkylene-C(O)—,—O-alkylene-OC(O)—, or a bond; whereinP₂ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;R₁₄ and R₁₅ are as defined above;R₁₄ and R₁₅ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring optionally incorporating one ortwo ring heteroatoms chosen from N, O, or S, which is unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected from thelist consisting of halo, methyl and methoxy;R₁₆ and R₁₇ are independently in each occurrence H or alkyl;R₁₆ and R₁₇ taken together with the atoms to which they attachoptionally form a 3- to 6-membered ring;R₁₈ and R₁₉ are as defined above;R₁₄ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₄ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;wherein Formula II includes enantiomers, pharmaceutically acceptablesalts, and polymorphs of the compounds of Formula II.

In one embodiment, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉,R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are H. In one embodiment, at leastone of R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂,R₃₃, R₃₄, R₃₅, and R₃₆ are deuterium.

In one embodiment, L₁ is a selected from the group consisting of—O-alkyl-C(O)—, —O-alkyl-OC(O)—. In one embodiment, L₁ is—O-alkylene-C(O)—. In one embodiment, L₁ is —O-alkylene-OC(O)—. In oneembodiment, the alkylene group of claim 41 is a C1-C5 alkylene group. Inone embodiment, the alkylene group of claim 41 is a C1 alkylene group.

In one sub-embodiment for Formula II, provided is a compound accordingto claim 41, wherein the compound is represented by Formula HA:

wherein L₁ and R₂ are defined as in Formula II.

Specific Compounds According to Formula II

The following represent specific compounds of Formula II:

Treprostinil 2-hydroxy lactone

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid carboxymethyl lactone Core Structure Formula III

In one other embodiment, the present invention also provides a compoundrepresented by Formula III:

wherein L₂ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;

X is NR₁₄, or O;

R₁₄ is selected from the group consisting of H, alkyl, cycloalkyl,alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substitutedheteroaryl, substituted arylalkyl, substituted heteroarylalkyl;R₁₆ and R₁₇ are independently in each occurrence H or alkyl;R₁₆ and R₁₇ taken together with the atoms to which they attachoptionally form a 3- to 6-membered ring; andR₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃,R₃₄, R₃₅, and R₃₆ are independently selected from the group consistingof H, deuterium;wherein Z is —OH, —OR₁₁, —N(R₁₁)R₁₂, —SR₁₁, or P₁;R₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, alkylcycloalkyl, substitutedalkylcycloalkyl, alkylcycloheteroalkyl, substitutedalkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substitutedalkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, orsubstituted alkylheteroaryl;R₁₂ is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,alkylcycloheteroalkyl, aryl, or heteroaryl;P₁ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;R₁₄ and R₁₅ are independently in each occurrence selected from the groupconsisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl,heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, substituted aryl, substituted heteroaryl, substitutedarylalkyl, and substituted heteroarylalkyl;R₁₄ and R₁₅ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring optionally incorporating one ortwo ring heteroatoms chosen from N, O, or S, which is unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halo, methyl, and methoxy;R₁₈ and R₁₉ are independently in each occurrence selected from the groupconsisting of hydrogen and alkyl, wherein the alkyl is unsubstituted orsubstituted with 1 substituent selected from the list consisting ofhalo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl),—CONH₂, aryl, and heteroaryl, wherein the aryl or heteroaryl areunsubstituted or substituted from the list consisting of alkyl, halo,haloalkyl, hydroxy, and alkoxy, haloalkoxy;R₁₄ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₄ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₅ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₅ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;wherein Formula III includes enantiomers, pharmaceutically acceptablesalts, and polymorphs of the compounds of Formula III.

In one embodiment, L₂ is selected from the group consisting of:

In one embodiment, at least one of R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆,R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are deuterium, orthey are all hydrogen.

One particular sub-embodiment of Formula III includes a compoundrepresented by Formula IIIA:

wherein Z and L₂ are defined as in Formula III.

SPECIFIC EXAMPLES OF FORMULA III COMPOUNDS

The following compounds represent specific examples of Formula IIIcompounds:

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester 2,3-maleate Core Structure for Formula IV Compounds

Another embodiment is a compound represented by Formula IV, whereinunlike in Formula II, the L₁ group links to R₂ rather than R₁:

R₁ is selected from the group consisting of H and P₂;R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃,R₃₄, R₃₅, and R₃₆ are independently selected from the group consistingof H and deuterium;L₁ is a selected from the group consisting of —O-alkylene-C(O)—,—O-alkylene-OC(O)—, or a bond; whereinP₂ is selected from the group consisting of:

wherein,m is 1, 2, 3, or 4;R₁₄ and R₁₅ are independently in each occurrence selected from the groupconsisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl,heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, substituted aryl, substituted heteroaryl, substitutedarylalkyl, and substituted heteroarylalkyl;R₁₄ and R₁₅ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring optionally incorporating one ortwo ring heteroatoms chosen from N, O, or S, which is unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halo, methyl, and methoxy;R₁₆ and R₁₇ are independently in each occurrence H or alkyl;R₁₆ and R₁₇ taken together with the atoms to which they attachoptionally form a 3- to 6-membered ring;R₁₈ and R₁₉ are independently in each occurrence selected from the groupconsisting of hydrogen and alkyl, wherein the alkyl is unsubstituted orsubstituted with 1 substituent selected from the list consisting ofhalo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl),—CONH₂, aryl, and heteroaryl, wherein the aryl or heteroaryl areunsubstituted or substituted from the list consisting of alkyl, halo,haloalkyl, hydroxy, and alkoxy, haloalkoxy;R₁₄ and R₁₈ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;R₁₄ and R₁₉ taken together with the atoms to which they attachoptionally form a 5- to 7-membered ring;wherein Formula IV includes enantiomers, pharmaceutically acceptablesalts, and polymorphs of the compounds of Formula IV.

In one embodiment, at least one of R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆,R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are deuterium, orthey are all hydrogen.

In a particular embodiment of Formula IV, a compound is represented byFormula IVA:

wherein L₁ and R₁ are defined as in Formula IV.

Similar approaches can be used to make and use Formula IV compounds asfor Formula II compounds.

EMBODIMENTS FROM PRIORITY PROVISIONAL 61/751,608

One embodiment from the priority provisional is a compound according toFormula (IAA).

wherein,R₁₀₀ and R₂₀₀ are independently selected from the group consisting of H,CONR₉₀₀R₁₀₀₀, CR₉₀₀R₁₀₀₀OCOP₃R₉₀₀R₁₀₀₀ wherein, R₉₀₀ and R₁₀₀₀ areindependently selected from H, alkyl, and cycloalkyl.R₃₀₀, R₄₀₀, R₅₀₀, R₆₀₀, R₇₀₀ and R₈₀₀ is independently selected from thegroup consisting of H and deuterium.

X is O, NHR₁₂₀₀, or S

P₃ is N or O

R₁₁₀₀ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,alkylcycloheteroalkyl, aryl, heteroaryl;R₁₂₀₀ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,alkylcycloheteroalkyl, aryl, heteroaryl.

In one embodiment, R₁₀₀, R₂₀₀ are H. In one embodiment, R₃₀₀, R₄₀₀,R₅₀₀, R₆₀₀, R₇₀₀ and R₈₀₀ are H. In one embodiment, X is O. In oneembodiment, R₁₁₀₀ is selected from

In one embodiment, X is NHR₁₂₀₀.

In one embodiment, R₁₁₀₀ is chosen from

In one embodiment, X is O. In one embodiment, R₃₀₀, R₄₀₀, R₅₀₀, R₆₀₀,R₇₀₀ and R₈₀₀ are H. In one embodiment, R₁₁₀₀ is alkyl.

Another embodiment from the priority provisional is a compound ofFormula II(AA) represented by:

wherein,R₂₀₀₀ is independently selected from the group consisting of H,CONR₉₀₀₀R₁₀₀₀₀, CR₉₀₀₀R₁₀₀₀₀OCOPR₉₀₀₀R₁₀₀₀₀. wherein, R₉₀₀₀ and R₁₀₀₀₀are independently selected from H, alkyl, cycloalkyl.R₃₀₀₀, R₄₀₀₀, R₅₀₀₀, R₆₀₀₀, R₇₀₀₀ and R₈₀₀₀ is independently selectedfrom the group consisting of H, deuterium.

X is O, NR₁₂₀₀₀, S P is N, O

R₁₂₀₀₀ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,alkylcycloheteroalkyl, aryl, heteroaryl.n is an integer between 1-7; and enantiomers of Formula II(AA),pharmaceutically acceptable salts of the compounds of Formula II(AA) andpolymorphs of Formula II(AA).

Another embodiment from the priority provisional is a compound havingFormula III(AA):

Wherein,

R₁₁ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,alkylcycloheteroalkyl, aryl, heteroaryl.wherein R₀₃, R₀₄, R₀₅, R₀₆, R₀₇ and R₀₈ is independently selected fromthe group consisting of H, deuterium.wherein, X is O, NR₀₁₂, SR₀₁₂ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,alkylcycloheteroalkyl, aryl, heteroaryl.

Y is C═O,

and enantiomers of the compound of formula III(AA); and pharmaceuticallyacceptable salts of the compounds of Formula III(AA) and polymorphs ofFormula III(AA).

Methods of Making for Formula I Compounds

Organic synthesis is used to make the compounds. See, for example,March's Advanced Organic Chemistry, 6^(th) Ed., Wiley, 2007.

The compounds of formula I where R1═R2═H can be synthesized according toscheme 1 by starting with the compound of formula I where Z is OH and R1is H and R2 is PG which represents a protective group as described inProtective Groups in Organic Synthesis by Greene and Wuts. Thecarboxylic acid is activated using coupling conditions which involve theuse of an activating agent, including but not limited to EDC, DCC, DIC,BOP, HATU, HBTU, CDI, thionyl chloride, or oxalyl chloride. Couplingconditions may also include or not include an additive, including butnot limited to DMF, HOSu, HOBT, or HOAT, and may or may not include oneor more nucleophilic or non-nucleophilic bases or additives including,but not limited to DMAP, TEA, DIPEA, N-methylmorpholine, pyridine,and/or imidazole. Coupling conditions also may be run in a suitablesolvent or solvent mixture including, but not limited to DCM, THF, DMF,dioxane, ethyl acetate, acetonitrile. The activated acid can be isolatedand purified or can be treated directly with ZH. Alternately, ZH can bepresent during the coupling conditions. Representative examples ofcoupling conditions and definitions of the activating agents, additivesand bases can be found in in Handbook of Reagents for Organic Synthesis:Activating Agents and Protecting Groups, John Wiley and Sons. Theresulting compound of formula I where Z is not OH, R1 is H and R2 is PGis deprotected using deprotection conditions suitable to the type ofprotective group represented by PG to give the compound of formula I.Examples of suitable deprotection conditions can be found in ProtectiveGroups in Organic Synthesis by Greene and Wuts.

The compound of formula I where R1═R2 or where R1 is H can besynthesized according to scheme 2 starting from the compound of formulaI where R1═R2═H by employing acylation conditions and the reactivemolecule ROH or RY where Y is a leaving group including, but not limitedto halogen, sulfonyl, phosphoryl, or acyl. In the case where thereactive molecule ROH is used, acylation conditions are identical tocoupling conditions as described above. In the case where the reactivemolecule RY is used, the acylation conditions may or may not include oneor more nucleophilic or non-nucleophilic bases or additives includingbut not limited to DMAP, TEA, DIPEA, N-methylmorpholine, pyridine,and/or imidazole and may be run in a suitable solvent or solvent mixtureincluding, but not limited to DCM, THF, DMF, dioxane, ethyl acetate, andacetonitrile.

The compounds of formula I where R2 is H can be synthesized according toscheme 3 starting from the compound of formula I where R1 is H and R2 isPG as defined above, by employing acylation conditions using ROH or RYas defined above followed by deprotection conditions as defined above.

Method of Making Formula II Compounds

The compounds of scheme II can be synthesized according to Scheme 4starting from the compound of scheme I where Z is OH and R2 is PG asdefined above, by employing lactonization conditions. Examples oflactonization conditions can be found in Chemical Reviews (2007), 107,239 and Beilstein Journal of Organic Chemistry (2012), 8, 1344, andinclude, but are not limited to 2,4,6-trichlorobenzoic anhydride, TEAand DMAP; 4-nitrobenzoic anhydride, TEA, and DMAP;2-chloro-1-methylpyridinium iodide and tributyl amine; 2,2′-dipyridyldisulfide and triphenylphosphine; and the all the reactions in thecoupling conditions and acylation conditions described above. Thelactonization reactions may be run in a suitable solvent or solventmixture including, but not limited to DCM, THF, DMF, dioxane, ethylacetate, acetonitrile and toluene.

Method of Making Formula III Compounds

The compounds of formula III can be synthesized according to Scheme 5starting with the compound of formula I where R1═R2═H, by reacting withan activated carbonyl equivalent including but not limited to phosgene,carbonyl diimidazole, or 4-nitrophenyl chloroformate, in the presence orabsence of one or more nucleophilic or non-nucleophilic bases oradditives including but not limited to DMAP, TEA, DIPEA,N-methylmorpholine, pyridine, and/or imidazole and may be run in asuitable solvent or solvent mixture including, but not limited to DCM,THF, DMF, dioxane, ethyl acetate, acetonitrile, and toluene.

Compositions

The compounds described herein can be used alone or in combination withother components as known in the art. In particular, formulations ofmultiple ingredients can be prepared that are adapted for use inprophylactic and therapeutic treatments. The composition can be in theform of, for example, a solid, liquid, semi-solid, solution, suspension,or emulsion formulation. Water can be used as a formulation agent. Itcan be in pure form or combined with one or more excipients.

In one embodiment, the compound is formulated in matrix form, comprisinga matrix material in which drug is contained or dispersed. The matrixmaterial further controls release of the drug by controlling dissolutionand/or diffusion of the drug from the reservoir, and may enhancestability of the drug molecule while stored in the reservoir. In oneembodiment, the drug is formulated with an excipient material that isuseful for accelerating release, e.g., a water-swellable material thatcan aid in pushing the drug out of the reservoir and through any tissuecapsule over the reservoir. Examples include hydrogels and osmoticpressure generating agents known in the art. In another embodiment, thedrug is formulated with a penetration enhancer(s). The penetrationenhancer further controls release of the drug by facilitating transportof the drug across the skin into the local administration site orsystemic delivery.

More particularly, the drug can be dispersed in a matrix material, tofurther control the rate of release of drug. This matrix material can bea “release system,” as described in U.S. Pat. No. 5,797,898, thedegradation, dissolution, or diffusion properties of which can provide amethod for controlling the release rate of the chemical molecules.

The release system may provide a temporally modulated release profile(e.g., pulsatile release) when time variation in plasma levels isdesired or a more continuous or consistent release profile when aconstant plasma level as needed to enhance a therapeutic effect, forexample. Pulsatile release can be achieved from an individual reservoir,from a plurality of reservoirs, or a combination thereof. For example,where each reservoir provides only a single pulse, multiple pulses(i.e., pulsatile release) are achieved by temporally staggering thesingle pulse release from each of several reservoirs. Alternatively,multiple pulses can be achieved from a single reservoir by incorporatingseveral layers of a release system and other materials into a singlereservoir. Continuous release can be achieved by incorporating a releasesystem that degrades, dissolves, or allows diffusion of moleculesthrough it over an extended period. In addition, continuous release canbe approximated by releasing several pulses of molecules in rapidsuccession (“digital” release). The active release systems describedherein can be used alone or on combination with passive release systems,for example, as described in U.S. Pat. No. 5,797,898.

The pharmaceutical agent can be formulated with one or morepharmaceutically acceptable excipients. Representative examples includebulking agents, wetting agents, stabilizers, crystal growth inhibitors,antioxidants, antimicrobials, preservatives, buffering agents (e.g.,acids, bases), surfactants, desiccants, dispersants, osmotic agents,binders (e.g., starch, gelatin), disintegrants (e.g., celluloses),glidants (e.g., talc), diluents (e.g., lactose, dicalcium phosphate),color agents, lubricants (e.g., magnesium stearate, hydrogenatedvegetable oils) and combinations thereof. In some embodiments, theexcipient is a wax or a polymer. In one embodiment, the polymercomprises polyethylene glycol (PEG), e.g., typically one having amolecular weight between about 100 and 10,000 Daltons (e.g., PEG 200,PEG 1450). In another embodiment, the polymer comprises poly lactic acid(PLA), poly glycolic acid (PGA), copolymers thereof (PLGA), orethyl-vinyl acetate (EVA) polymers. In yet another embodiment, theexcipient material comprises a pharmaceutically acceptable oil (e.g.,sesame oil).

In one embodiment, the excipient material includes a saturated drugsolution. That is, the excipient material comprises a liquid solutionformed of the drug dissolved in a solvent for the drug. The solution issaturated so that the solvent does not dissolve the solid matrix form ofthe drug. The saturated solution acts as a non-solvent excipientmaterial, substantially filling pores and voids in the solid matrix.

In another embodiment, the excipient material comprises apharmaceutically-acceptable perhalohydrocarbon or unsubstitutedsaturated hydrocarbon. See, for example, U.S. Pat. No. 6,264,990 toKnepp et al., which describes anhydrous, aprotic, hydrophobic, non-polarliquids, such as biocompatible perhalohydrocarbons or unsubstitutedsaturated hydrocarbons, such as perfluorodecalin, perfluorobutylamine,perfluorotripropylamine, perfluoro-N-methyldecahydroquindine,perfluoro-octohydro quinolidine, perfluoro-N-cyclohexylpyrilidine,perfluoro-N,N-dimethylcyclohexyl methylamine,perfluoro-dimethyl-adamantane, perfluorotri-methylbicyclo (3.3.1)nonane, bis(perfluorohexyl)ethene, bis(perfluorobutyl)ethene,perfluoro-1-butyl-2-hexyl ethene, tetradecane, methoxyflurane andmineral oil.).

In one embodiment, the pharmaceutically acceptable excipient materialcomprises dimethyl sulfoxide (DMSO), glycerol, or ethanol. Mixtures ofcompounds according to Formulae I, II, III, and IV can be used.

EXAMPLES

Additional embodiments are provided in the following, non-limitingexamples. Four assays on compounds were carried out by the followingmethods with the results shown in Table I:

(Test 1) Human liver microsomal stability assay was conducted byincubating 0.5 uM test compounds at 37° C. for up to 45 minutes in 50 mMof potassium phosphate buffer (pH 7.4) containing 0.5 mg of microsomalprotein and 50 μL of NADPH generating system (7.8 mg of glucose6-phosphate, 1.7 mg of NADPH and 6 U of glucose 6-phosphatedehydrogenase) per mL in 2% w/v of sodium bicarbonate). At 0, 5, 15, 30and 45 min., an aliquot was taken, quenched with internal standardcontaining stop solution. No co-factor controls at 45 minutes were alsoprepared. After incubation, the samples were analyzed by LC-MS/MS. Peakarea ratios of analyte to internal standard were used to calculate theintrinsic clearance. The intrinsic clearance (CLint) was determined fromthe first order elimination constant by non-linear regression. Formationof the active drug Compound A over the time course was also monitored byLCMS/MS analysis.

(Test 2) Human plasma stability assay was conducted by incubating 0.5 uMtest compounds at 37° C. for up to 120 minutes in heparinated humanplasma. At 0, 5, 15, 30, 60 and 120 min., an aliquot was taken, quenchedwith internal standard containing stop solution. After incubation, thesamples were analyzed by LC-MS/MS. Peak area ratios of analyte tointernal standard were used to calculate the half-life. Formation of theactive drug Compound A over the time course was also monitored byLCMS/MS analysis.

(Test 3) Human skin homogenate stability assay was conducted, in thesame way as in human liver microsomal stability assay, by incubating 0.5uM test compounds at 37° C. for up to 45 minutes in 50 mM of potassiumphosphate buffer (pH 7.4) containing 0.5 mg of human skin homogenateprotein and 50 μL of NADPH generating system (7.8 mg of glucose6-phosphate, 1.7 mg of NADPH and 6 U of glucose 6-phosphatedehydrogenase) per mL in 2% w/v of sodium bicarbonate). At 0, 5, 15, 30and 45 min., an aliquot was taken, quenched with internal standardcontaining stop solution. No co-factor controls at 45 minutes were alsoprepared. After incubation, the samples were analyzed by LC-MS/MS. Peakarea ratios of analyte to internal standard were used to calculate theintrinsic clearance. The intrinsic clearance (CLint) was determined fromthe first order elimination constant by non-linear regression. Formationof the active drug Compound A over the time course was also monitored byLCMS/MS analysis.

(Test 4) Human hepatocyte stability assay was conducted by incubating0.5 uM test compound at 37° C. for up to 240 minutes. Cryopreservedhuman hepatocytes were obtained from Celsis IVT (Baltimore Md.). Cellswere thawed according to vendor's instructions and were suspended inWilliam's Medium E to 0.5 million cells/mL. Test compounds were spikedinto the cell suspension to initiate the reactions. At 0, 10, 30, 60,120 and 240 min., an aliquot was taken, quenched with internal standardcontaining stop solution. After incubation, the samples were analyzed byLC-MS/MS. Peak area ratios of analyte to internal standard were used tocalculate the intrinsic clearance. The intrinsic clearance (CLint) wasdetermined from the first order elimination constant by non-linearregression. Formation of the active drug Compound A over the time coursewas also monitored by LCMS/MS analysis.

Assay results (half life) are shown in Table I. In Table I, the code forthe results of the assay testing are:

A=<15 min

B=15-30 min

C=31-60 min

D=>60 min

TABLE I Test Compound MW m/z Test 1 Test 2 Test 3 4 No. (g/mol) [M +Na]+ T_(1/2) T_(1/2) T_(1/2) T_(1/2) 1 444.62 467.62 A A 2 443.63 466.63A D C 3 503.68 526.68 4 450.6 473.6 A A 5 460.62 483.62 A A 6 476.62499.62 A A A 390 413 7 433.59 456.59 A D B 8 432.61 455.61 A 9 434 457 A10 448 471 A 11 447 470 A D 12 461 484 A D 13 475 498 A D A 14 471 494 AD D A 57 372 395 D D D 15 404 427 A A A 16 460 483 A B A 17 460 483 A CA 18 474 497 A D D 19 484 507 A C A 20 432 455 A C A 21 521 544 A D 22488 511 A D D 23 488 511 A D 24 472 495 A D 25 476 499 A D C 26 446 489A C B 27 532 555 A D 28 446 469 A C

EXAMPLES FOR SYNTHESIS

In addition, the following representative syntheses are shown forcompounds according to Formulae I, II, and III.

Example 1 Synthesis of:2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(2,2,2-trifluoro-ethyl)-acetamide

A solution of{2-Hydroxy-1-[3-(tetrahydro-pyran-2-yloxy)-octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}-aceticacid (94 mg, 0.2 mmol), trifluoroethylamine (54 mg, 0.6 mmol) and DIPEA(104 μl, 0.6 mmol) in DMF (2 ml) was treated with HATU and stirred 24 hrat RT. The reaction mixture was diluted with MTBE and washed withsaturated sodium bicarbonate solution and brine, dried over sodiumsulfate and concentrated under vacuum. The residue was purified bysilica gel chromatography. This resulting material was dissolved in MeOH(4 ml), treated with Amberlite IR120H and stirred 24 hr. The reactionmixture was filtered and concentrated to yield2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(2,2,2-trifluoro-ethyl)-acetamide(46 mg) as an oil. ¹HNMR (400 MHz, CDCl₃) δ 7.06 (d, 1H, J=7.6); 6.80(d, 1H, J=7.2); 6.63 (d, 1H, J=8.0); 4.86 (quint., 1H, J=6.4); 4.60 (s,2H); 3.7-3.8 (m, 1H); 3.55-3.65 (m, 1H); 2.85-2.95 (ddd, 1H); 2.70-2.80(dd, 1H); 2.50-2.60 (ddd, 1H); 2.40-2.50 (dd, 1H); 2.15-2.3 (m, 2H);1.75-1.95 (m, 2H); 1.24-1.70 (m, 17H); 1.20 (d, 3H, J=6.4); 0.85-0.95(m, 8H); MS: m/z 494 [M+Na]⁺

Example 2 Synthesis of:[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2-dimethyl-propyl ester

A solution of{2-Hydroxy-1-[3-(tetrahydro-pyran-2-yloxy)-octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}-aceticacid (47 mg, 0.1 mmol), 3-methyl-2-butanol (26 mg, 0.3 mmol) and DMAP(12 mg, 0.1 mmol) in DCM (1 ml) was treated with EDC (26 mg, 0.14 mmol)and stirred 24 hr at RT. The reaction mixture was diluted with MTBE andwashed with saturated sodium bicarbonate solution and brine, dried oversodium sulfate and concentrated under vacuum. The residue was purifiedby silica gel chromatography. This resulting material was dissolved inMeOH/THE (4 ml), treated with Amberlite IR120H and stirred 24 hr.

The reaction mixture was filtered and concentrated to yield[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2-dimethyl-propyl ester (16 mg) as an oil. ¹HNMR (400 MHz, CDCl₃)δ 7.06 (d, 1H, J=7.6); 6.80 (d, 1H, J=7.2); 6.63 (d, 1H, J=8.0); 4.86(quint., 1H, J=5.6); 4.60 (s, 2H); 3.7-3.8 (m, 1H); 3.55-3.80 (m, 1H);3.55-3.70 (m, 1H); 2.85-2.95 (dd, 1H); 2.50-2.80 (dd, 1H); 2.50-2.60(dd, 1H); 2.40-2.60 (dd, 1H); 2.15-2.30 (m, 2H); 1.75-1.95 (m, 2H);1.35-1.80 (m, 17H); 1.19 (d, 3H, J=6.4); 0.85-0.95 (m, 8H); MS: m/z 483[M+Na]⁺

Example 3 Synthesis of: Treprostinil 2-Hydroxy Lactone

A solution of{2-Hydroxy-1-[3-(tetrahydro-pyran-2-yloxy)-octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}-aceticacid (47 mg, 0.1 mmol) and DMAP (26 mg, 0.2 mmol) in DCM (1 ml) wastreated with 2,4,6-trichlorobenzoyl chloride (27 mg, 0.11 mmol) andstirred 24 hr at RT. The reaction mixture was diluted with ethyl acetateand washed with saturated sodium bicarbonate solution and brine, driedover sodium sulfate and concentrated under vacuum. The residue waspurified by silica gel chromatography. This resulting material wasdissolved in MeOH/THE (4 ml), treated with Amberlite IR120H and stirred24 hr. The reaction mixture was filtered and concentrated to yieldtreprostinil 2-hydroxy lactone (8 mg) as an oil. ¹HNMR (400 MHz, CDCl₃)δ 7.03 (dd, 1H, J=8.4 Hz, J=7.6 Hz); 6.74 (d, 1H, J=7.6 Hz); 6.55 (d,1H, J=8.4 Hz) 4.53 (m, 1H); 4.46 (d, 1H, J=15.2 Hz); 4.31 (d, 1H, J=15.2Hz); 3.53 (m, 1H); 2.5 (m, 1H); 2.8 (dd, 1H); 2.6 (dd, 1H); 2.2-2.55 (m,4H); 1.53 (m, 4H); 1.35-1.47 (m, 4H); 1.3 (m, 6H); 0.89 (m, 3H); MS: m/z395 [M+Na]⁺

Example 4 Synthesis of: Cyclopropanecarboxylic acid1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ylester

A solution of[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester (32 mg, 0.06 mmol), DIPEA (31 μl, 0.18 mmol) and DMAP(1 crystal) in DCM (2 ml) was treated with cyclopropanecarbonyl chloride(8 μl, 0.08 mmol) and stirred for 24 hr at RT under nitrogen. Thereaction mixture was diluted with MTBE and washed with saturated sodiumbicarbonate solution and brine, dried over sodium sulfate andconcentrated under vacuum. The residue was purified by silica gelchromatography. This resulting material was dissolved in MeOH/THE (4ml), treated with Amberlite IR120H and stirred 24 hr. The reactionmixture was filtered and concentrated to yield cyclopropanecarboxylicacid1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ylester (32 mg) as an oil. ¹HNMR: (400 MHz, DMSO-d₆) δ 7.06 (d, 1H,J=7.6); 6.80 (d, 1H, J=7.2); 6.63 (d, 1H, J=8.8); 4.78 (s, 2H); 4.1-4.2(m, 1H); 4.05-4.50 (m, 1H); 3.68 (s, 3H); 2.6-2.8 (m, 2H); 2.4-2.5 (m,2H); 2.20-2.35 (m, 1H); 2.10-2.20 (m, 1H); 1.8-1.95 (m, 1H); 1.10-1.16(m, 15H); 0.95-1.10 (m, 1H); 0.70-0.90 (m, 7H); MS: m/z 495 [M+Na]⁺

Example 5 Synthesis of Formula III Compound

A solution of acrylic acid1-[2-(2-acryloyloxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexylester (51 mg, 0.1 mmol) in chloroform (20 ml) is treated with a solutionof (PCy3)2Cl2Ru=CHPh (19 mg, 0.023 mmol) in chloroform (3 ml) andstirred 24 hr at RT. TEA (1 ml) is added and the solution isconcentrated under vacuum. The residue is purified by silica gelchromatography to yield the title compound.

Additional synthetic schemes are shown below:

Example 6 Formula I Compound

Example 7 Formula I Compound

1. A compound represented by Formula (I)

wherein, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are independently H or deuterium; Z is —OH, —OR₁₁, —N(R₁₁)R₁₂, —SR₁₁, or P₁; R₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl; R₁₂ is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl; P₁ is selected from the group consisting of:

wherein, m is 1, 2, 3, or 4; R₁₄ and R₁₅ are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; R₁₄ and R₁₅ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R₁₈ and R₁₉ are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R₁₄ and R₁₈ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; R₁₄ and R₁₉ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; R₁₅ and R₁₈ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; R₁₅ and R₁₉ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; and, R₁ and R₂ are independently H or P₂, wherein at least one of R₁ and R₂ is P₂, wherein P₂ is selected from the group consisting of:

wherein, m is 1, 2, 3, or 4; R₁₄ and R₁₅ are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; R₁₄ and R₁₅ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R₁₆ and R₁₇ are independently in each occurrence H or alkyl; R₁₆ and R₁₇ taken together with the atoms to which they attach optionally form a 3- to 6-membered ring; R₁₈ and R₁₉ are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R₁₄ and R₁₈ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; R₁₄ and R₁₉ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; wherein Formula I includes enantiomers, pharmaceutically acceptable salts, and polymorphs of the compounds of Formula I.
 2. The compound of claim 1, wherein R₁ is P₂ and R₂ is H.
 3. The compound of claim 1, wherein R₁ is H and R₂ is P₂.
 4. The compound of claim 1, wherein R₁ is P₂ and R₂ is P₂.
 5. The compound of claim 1, wherein P₂ is selected from the group consisting of:


6. The compound of claim 1, wherein P₂ is selected from the group consisting of:


7. The compound of claim 1, wherein P₂ is selected from the group consisting of:


8. The compound of claim 1, wherein P₂ is selected from the group consisting of:


9. The compound of claim 1, wherein P₂ is selected from the group consisting of:


10. The compound of claim 1, wherein P₂ is selected from the group consisting of:


11. The compound of claim 1, wherein P₂ is selected from the group consisting of:


12. The compound of claim 1, wherein P₂ is selected from the group consisting of:


13. The compound of claim 1, wherein P₂ is selected from the group consisting of:


14. The compound of claim 1, wherein P₂ is selected from the group consisting of:


15. The compound of claim 1, wherein P₂ is selected from the group consisting of:


16. The compound of claim 1, wherein R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are H.
 17. A compound according to claim 1, wherein at least one of R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are deuterium.
 18. The compound of claim 1, wherein Z is −OR₁₁, —N(R₁₁)R₁₂, or P₁.
 19. The compound of claim 1, wherein Z is P₁.
 20. The compound of claim 1, wherein Z is —OH, —OR₁₁, —N(R₁₁)R₁₂, or P₁.
 21. The compound of claim 1, wherein Z is —OH.
 22. The compound of claim 1, wherein Z is not —OH and R₁₁ is not unsubstituted or substituted benzyl.
 23. A compound according to claim 1, wherein the compound is represented by Formula (IA)

wherein, Z is —OH, —OR₁₁, or P₁; R₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, P₁ is selected from the group consisting of:

wherein, m is 1, 2, 3, or 4; R₁₄ and R₁₅ are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; R₁₄ and R₁₅ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; and, R₁ and R₂ are independently H or P₂, wherein at least one of R₁ and R₂ is P₂, wherein P₂ is selected from the group consisting of:

wherein, R₁₄ is selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; wherein Formula IA includes enantiomers, pharmaceutically acceptable salts, and polymorphs of the compounds of Formula IA.
 24. A compound according to Formula (I)

wherein, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are independently H or deuterium; wherein Z is −OR₁₁, —N(R₁₁)R₁₂, —SR₁₁, or P₁; R₁₁ is branched alkyl, haloalkyl, halocycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, bicycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, alkylaryl, substituted alkylaryl, alkylheteroaryl, substituted alkylheteroaryl; heteroaryl, substituted heteroaryl; R₁₂ is H, branched alkyl, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl; P₁ is selected from the group consisting of:

wherein, m is 1, 2, 3, or 4; R₁₄ and R₁₅ are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; R₁₄ and R₁₅ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R₁₈ and R₁₉ are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R₁₄ and R₁₈ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; R₁₄ and R₁₉ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; R₁₅ and R₁₈ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; R₁₅ and R₁₉ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; and, R₁ and R₂ are independently H or P₂, wherein P₂ is selected from the group consisting of:

wherein, m is 1, 2, 3, or 4; R₁₄ and R₁₅ are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; R₁₄ and R₁₅ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R₁₆ and R₁₇ are independently in each occurrence H or alkyl; R₁₆ and R₁₇ taken together with the atoms to which they attach optionally form a 3- to 6-membered ring; R₁₈ and R₁₉ are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R₁₄ and R₁₈ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; R₁₄ and R₁₉ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; wherein Formula I includes enantiomers, pharmaceutically acceptable salts, and polymorphs of the compounds of Formula I.
 25. The compound of claim 24, wherein Z is −OR₁₁.
 26. The compound of claim 24, wherein Z is —N(R₁₁)R₁₂.
 27. The compound of claim 24, wherein Z is —SR₁₁.
 28. The compound of claim 24, wherein Z is P₁.
 29. The compound of claim 24, wherein Z is OR₁₁ and R₁₁ is bicycloalkyl, alkylcycloalkyl, or alkylcycloheteroalkyl.
 30. The compound of claim 24, wherein R₁₁ is haloalkyl.
 31. The compound of claim 24, wherein R₁₁ is fluoroalkyl.
 32. The compound of claim 24, wherein R₁ is hydrogen and R₂ is P₂.
 33. The compound of claim 24, wherein R₁ is P₂ and R₂ is hydrogen.
 34. The compound of claim 24, wherein R₁ is P₂ and R₂ is P₂.
 35. The compound of claim 24, wherein R₁ and R₂ are each hydrogen.
 36. A compound according to claim 24, wherein R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are H.
 37. A compound according to claim 24, wherein at least one of R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are deuterium.
 38. A compound according to Formula (IAA).

wherein, R₁₀₀ and R₂₀₀ are independently selected from the group consisting of H, CONR₉₀₀R₁₀₀₀, CR₉₀₀R₁₀₀₀OCOP₃R₉₀₀R₁₀₀₀ wherein, R₉₀₀ and R₁₀₀₀ are independently selected from H, alkyl, and cycloalkyl. R₃₀₀, R₄₀₀, R₅₀₀, R₆₀₀, R₇₀₀ and R₈₀₀ is independently selected from the group consisting of H and deuterium. X is O, NHR₁₂₀₀, or S P₃ is N or O R₁₁₀₀ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl; R₁₂₀₀ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl.
 39. A compound of claim 38 wherein R₁₀₀, R₂₀₀ are H.
 40. A compound of claim 39 wherein R₃₀₀, R₄₀₀, R₅₀₀, R₆₀₀, R₇₀₀ and R₈₀₀ are H.
 41. A compound of claim 40 wherein X is O.
 42. A compound of claim 41 wherein R₁₁₀₀ is selected from


43. A compound of claim 39 wherein X is NHR₁₂₀₀.
 44. A compound of claim 43 wherein R₁₁₀₀ is chosen from


45. A compound of claim 38 wherein X is O.
 46. A compound of claim 45 wherein R₃₀₀, R₄₀₀, R₅₀₀, R₆₀₀, R₇₀₀ and R₈₀₀ are H.
 47. A compound of claim 46 wherein R₁₁₀₀ is alkyl.
 48. A compound represented by Formula II:

wherein, R₂ is selected from the group consisting of H and P₂; R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are independently selected from the group consisting of H and deuterium; L₁ is a selected from the group consisting of —O-alkylene-C(O)—, —O-alkylene-OC(O)—, or a bond; wherein P₂ is selected from the group consisting of:

wherein, m is 1, 2, 3, or 4; R₁₄ and R₁₅ are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; R₁₄ and R₁₅ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R₁₆ and R₁₇ are independently in each occurrence H or alkyl; R₁₆ and R₁₇ taken together with the atoms to which they attach optionally form a 3- to 6-membered ring; R₁₈ and R₁₉ are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R₁₄ and R₁₈ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; R₁₄ and R₁₉ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; wherein Formula II includes enantiomers, pharmaceutically acceptable salts, and polymorphs of the compounds of Formula II.
 49. The compound of claim 48, wherein R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are H.
 50. A compound according to claim 48, wherein at least one of R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are deuterium.
 51. The compound of claim 48, wherein L₁ is —O-alkylene-C(O)—.
 52. The compound of claim 48, wherein L₁ is —O-alkylene-OC(O)—.
 53. The compound of claim 48, wherein L₁ is a bond.
 54. The compound of claim 48, wherein the alkylene group is a C₁-C₅ alkylene group.
 55. The compound of claim 48, wherein the alkylene group is a C₁ alkylene group.
 56. A compound according to claim 48, wherein the compound is represented by Formula IIA:

wherein L₁ and R₂ are defined as in claim
 48. 57. A compound of Formula II(AA)

wherein, R₂₀₀₀ is independently selected from the group consisting of H, CONR₉₀₀₀R₁₀₀₀₀, CR₉₀₀₀R₁₀₀₀₀OCOPR₉₀₀₀R₁₀₀₀₀. wherein, R₉₀₀₀ and R₁₀₀₀₀ are independently selected from H, alkyl, cycloalkyl. R₃₀₀₀, R₄₀₀₀, R₅₀₀₀, R₆₀₀₀, R₇₀₀₀ and R₈₀₀₀ is independently selected from the group consisting of H, deuterium. X is O, NR₁₂₀₀₀, S P is N, O R₁₂₀₀₀ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl. n is an integer between 1-7; and enantiomers of the compound of Formula II(AA); and Formula III(AA) includes enantiomers of Formula II(AA), pharmaceutically acceptable salts of the compounds of Formula II(a) and polymorphs of Formula II(AA).
 58. A compound represented by Formula III:

wherein L₂ is selected from the group consisting of:

wherein, m is 1, 2, 3, or 4; X is NR₁₄, or O; R₁₄ is selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl; R₁₆ and R₁₇ are independently in each occurrence H or alkyl; R₁₆ and R₁₇ taken together with the atoms to which they attach optionally form a 3- to 6-membered ring; and R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are independently selected from the group consisting of H and deuterium; wherein Z is —OH, —OR₁₁, —N(R₁₁)R₁₂, —SR₁₁, or P₁; R₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl, substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl; R₁₂ is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl; P_(i) is selected from the group consisting of:

wherein, m is 1, 2, 3, or 4; R₁₄ and R₁₅ are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; R₁₄ and R₁₅ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R₁₈ and R₁₉ are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R₁₄ and R₁₈ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; R₁₄ and R₁₉ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; R₁₅ and R₁₈ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; R₁₅ and R₁₉ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; wherein Formula III includes enantiomers, pharmaceutically acceptable salts, and polymorphs of the compounds of Formula III.
 59. The compound of claim 58, wherein L₂ is selected from the group consisting of:


60. A compound according to claim 58, wherein R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are H.
 61. A compound according to claim 58, wherein at least one of R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are deuterium.
 62. A compound according to claim 58, wherein the compound is represented by Formula IIIA:

wherein Z and L₂ are defined as in claim
 58. 63. A compound having Formula III(AA):

wherein, R₁₁ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl. wherein R₀₃, R₀₄, R₀₅, R₀₆, R₀₇ and R₀₈ is independently selected from the group consisting of H, deuterium. wherein, X is O, NR₀₁₂, S R₀₁₂ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, aryl, heteroaryl. Y is C═O, and enantiomers of the compound of formula III(AA); and pharmaceutically acceptable salts of the compounds of Formula III(AA) and polymorphs of Formula III(AA).
 64. A compound represented by Formula IV:

R₁ is selected from the group consisting of H and P₂; R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are independently selected from the group consisting of H and deuterium; L₁ is a selected from the group consisting of —O-alkylene-C(O)—, —O-alkylene-OC(O)—, or a bond; wherein P₂ is selected from the group consisting of:

wherein, m is 1, 2, 3, or 4; R₁₄ and R₁₅ are independently in each occurrence selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; R₁₄ and R₁₅ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, methyl, and methoxy; R₁₆ and R₁₇ are independently in each occurrence H or alkyl; R₁₆ and R₁₇ taken together with the atoms to which they attach optionally form a 3- to 6-membered ring; R₁₈ and R₁₉ are independently in each occurrence selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with 1 substituent selected from the list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH, —C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the aryl or heteroaryl are unsubstituted or substituted from the list consisting of alkyl, halo, haloalkyl, hydroxy, and alkoxy, haloalkoxy; R₁₄ and R₁₈ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; R₁₄ and R₁₉ taken together with the atoms to which they attach optionally form a 5- to 7-membered ring; wherein Formula IV includes enantiomers, pharmaceutically acceptable salts, and polymorphs of the compounds of Formula W.
 65. A compound according to claim 64, wherein the compound is represented by Formula IVA:

wherein L₁ and R₁ are defined as in claim
 64. 66. A composition comprising at least one compound according to claim 1 and at least one other component.
 67. A composition according to claim 66 formulated for transdermal delivery.
 68. A composition according to claim 66 formulated for transdermal delivery with a patch.
 69. A composition according to claim 66, further comprising at least one solvent.
 70. A composition of claim 63, wherein the amount of the compound according to claim 1 is adapted to provide a useful delivery profile for treatment of a human. 